title: Expression of ST3GAL4 leads to SLe(x) expression and induces c-Met activation and an invasive phenotype in gastric carcinoma cells.
abstract: Sialyl-Lewis X (SLe(x)) is a sialylated glycan antigen expressed on the cell surface during malignant cell transformation and is associated with cancer progression and poor prognosis. The increased expression of sialylated glycans is associated with alterations in the expression of sialyltransferases (STs). In this study we determined the capacity of ST3GAL3 and ST3GAL4 sialyltransferases to synthesize the SLe(x) antigen in MKN45 gastric carcinoma cells and evaluated the effect of SLe(x) overexpression in cancer cell behavior both in vitro and in vivo using the chicken chorioallantoic membrane (CAM) model. The activation of tyrosine kinase receptors and their downstream molecular targets was also addressed. Our results showed that the expression of ST3GAL4 in MKN45 gastric cancer cells leads to the synthesis of SLe(x) antigens and to an increased invasive phenotype both in vitro and in the in vivo CAM model. Analysis of phosphorylation of tyrosine kinase receptors showed a specific increase in c-Met activation. The characterization of downstream molecular targets of c-Met activation, involved in the invasive phenotype, revealed increased phosphorylation of FAK and Src proteins and activation of Cdc42, Rac1 and RhoA GTPases. Inhibition of c-Met and Src activation abolished the observed increased cell invasive phenotype. In conclusion, the expression of ST3GAL4 leads to SLe(x) antigen expression in gastric cancer cells which in turn induces an increased invasive phenotype through the activation of c-Met, in association with Src, FAK and Cdc42, Rac1 and RhoA GTPases activation.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto, IPATIMUP, Porto, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Gomes
authors.forename: Hugo
authors.initials: H
authors.lastname: Osório
authors.forename: Marta Teixeira
authors.initials: MT
authors.lastname: Pinto
authors.forename: Diana
authors.initials: D
authors.lastname: Campos
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Oliveira
authors.forename: Celso A
authors.initials: CA
authors.lastname: Reis
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000473:pathology; D004789:Enzyme Activation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016256:Lewis X Antigen / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009844:Oligosaccharides / Q000378:metabolism*; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D000080506:Sialyl Lewis X Antigen; D012799:Sialyltransferases / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D013450:Sulfones / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; C412373:AG 1879; D007211:Indoles; D016256:Lewis X Antigen; D009844:Oligosaccharides; D011743:Pyrimidines; D000080506:Sialyl Lewis X Antigen; D013450:Sulfones; D012799:Sialyltransferases; D019859:Proto-Oncogene Proteins c-met; D019061:src-Family Kinases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; C000722087:ST3GAL1 protein, human